Bactericidal activity and killing rate of serum in volunteers receiving ciprofloxacin alone or in combination with vancomycin.

Ten healthy volunteers received the following regimen on different days: vancomycin, 500 mg intravenously; ciprofloxacin, 200 mg intravenously; vancomycin plus ciprofloxacin. Concentrations in serum measured microbiologically at the end of infusion and 1 and 6 h after the end of infusion were, respectively (mean [standard deviation] in milligrams per liter): 32.3 (5.5), 14.2 (2.6), and 4 (0.9) for vancomycin and 3.12 (0.86), 0.78 (0.18), and 0.19 (0.05) for ciprofloxacin. Vancomycin concentration was not affected by the simultaneous administration of ciprofloxacin. The serum bacteriostatic and bactericidal (SBA) activities were measured 1 and 6 h after the end of infusion against five strains each of Staphylococcus aureus susceptible and resistant to oxacillin, Staphylococcus epidermidis susceptible and resistant to oxacillin, Corynebacterium strain JK, and Listeria monocytogenes and three strains of Mycobacterum fortuitum. Ciprofloxacin alone provided low SBAs against the tested strains even 1 h after administration. Vancomycin provided adequate SBAs against staphylococci and Corynebacterium strain JK 1 h after administration. None of the regimens tested showed adequate bactericidal activity against L. monocytogenes and M. fortuitum. The combination of vancomycin with ciprofloxacin was indifferent. This was confirmed by studying the rate of killing in serum. Vancomycin plus ciprofloxacin appeared to be promising for the empiric treatment of infection in immunocompromised patients.     

Bactericidal activity and killing rate of serum in volunteers receiving vancomycin or teicoplanin with and without amikacin given intravenously

We have studied the interaction between vancomycin or teicoplanin and amikacin in two groups of five volunteers randomized to receive either (a) vacomycin, amikacin, vancomycin+amikacin, or (b) teicoplanin, amikacin, teicoplanin+amikacin. Each administration was given on separate days, in random order with a 48 hours washout period between each infusion. The serum concentrations measured microbiologically at time 0, 1 and 6 h were: 42.6, 11.4 and 4.1 mg/l respectively for teicoplanin; 27.6, 13.9, and 4.2 mg/l for vancomycin, and 44.9, 17.8, and 1.9 mg/l for amikacin. Teicoplanin was also measured using a solid-phase enzyme-receptor assay (SPERA). The serum bactericidal titres and the rate of killing in serum were measured 1 and 6 h after infusion against Staphylococcus aureus susceptible or resistant to oxacillin (5 strains each), S. epidermidis susceptible and resistant to oxacillin (5 strains each), Corynebacterium JK (5 strains), Listeria monocytogenes (5 strains), and Mycobacterium fortuitum (3 strains). The addition of amikacin to either teicoplanin or vancomycin increased the serum bactericidal titres against staphylococci with the exception of oxacillin-resistant S. epidermidis. Teicoplanin+amikacin was the most active regimen against L. monocytogenes and was equivalent to vancomycin+amikacin against M. fortuitum. Teicoplanin alone and teicoplanin+amikacin had a significantly lower killing rate against staphylococci than amikacin alone.     

Bactericidal activity and killing rate of serum in volunteers receiving pefloxacin alone or in combination with ceftazidime, piperacillin or mezlocillin against Pseudomonas aeruginosa

The activity of the combination of pefloxacin with ceftazidime, piperacillin, or mezlocillin was compared to the activity of the same antibiotics given alone, by measurement of serum bactericidal titres and the rate of killing of ten strains of Pseudomonas aeruginosa. Three groups of five volunteers each received pefloxacin (12 mg/kg iv) with or without ceftazidime, piperacillin or mezlocillin (25 mg/kg iv). Serum samples were obtained at the end of the infusion. The mean serum concentration of pefloxacin at this time was 13.9 mg/l (3.2, S.D.). The activity of each of the three combinations was identical to the corresponding activity of the beta-lactam alone. However, the emergence of resistance to pefloxacin was prevented by ceftazidime (five out of five strains), and piperacillin (two out of five strains). We conclude that combinations of pefloxacin with beta-lactam antibiotics may not increase efficacy against P. aeruginosa.     

Bactericidal activity and killing rate of serum from volunteers receiving pefloxacin alone or in combination with amikacin.

Serum bactericidal activities (SBAs) were studied after intravenous administration of pefloxacin (8 mg/kg) and amikacin (7.5 mg/kg) alone or in combination to 15 human volunteers. About 10 strains each of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus were tested. The serum levels of pefloxacin were measured microbiologically by using E. coli KP 1976-712 as the test organism at 0, 30, 60, 120, and 720 min after infusion; at 0, 30, 60, and 720 min these levels were 7 +/- 1.4, 5 +/- 0.8, 4.5 +/- 0.7, and 2.1 +/- 0.6 mg/liter (mean +/- standard deviation), respectively, with a terminal half-life of 10 h. The serum levels of pefloxacin in the presence of amikacin were measured similarly; 1% sodium polyanethol sulfonate was added to the agar to inactivate amikacin. Treatment with pefloxacin alone resulted in high SBAs against E. coli, K. pneumoniae strains susceptible to cephalothin, and Staphylococcus aureus at the peak concentration; 81 to 100% of the sera had SBAs of greater than or equal to 1:8. However, treatment with pefloxacin alone resulted in low SBAs against K. pneumoniae strains resistant to cephalothin and P. aeruginosa; only 34% of the sera had SBAs of greater than or equal to 1:8. At trough concentrations the percentages of sera with SBAs greater than or equal to 1:8 were 75 to 83% (E. coli), 9 to 27% (K. pneumoniae), 0% (P. aeruginosa), and 10% (S. aureus). The combination of pefloxacin plus amikacin was most often additive; the peak activity was due to amikacin, and the trough activity was due to pefloxacin. Occasionally antagonism occurred with P. aeruginosa, K. pneumoniae, and S. aureus strains. These observations were confirmed by the killing curves in pooled serum obtained at peak and trough levels. Regrowth was observed for seven strains of P. aeruginosa treated with pefloxacin alone; amikacin seemed to prevent this phenomenon.     

Bactericidal activity and killing rate of serum in volunteers receiving teicoplanin alone or in combination with oral or intravenous rifampin.

A total of 10 volunteers, in two groups of 5 each, received the following on separate days: group 1,200 mg of teicoplanin intravenously (i.v.), 600 mg of rifampin orally, or teicoplanin-rifampin; group 2,400 mg of teicoplanin i.v., 300 mg of rifampin i.v. in 60 min, or teicoplanin-rifampin. Blood samples were obtained before, at the end, and at 1 and 6 h after the administration of the antibiotics. Bactericidal activity in serum (SBA) was measured in microtiter plates against 20 clinical isolates (five strains each) of oxacillin-susceptible and-resistant Staphylococcus aureus and Staphylococcus epidermidis. The endpoint of the SBA corresponded to 99.9% killing. Killing rates were measured in serum obtained at 1 and 6 h. The concentrations of each antibiotic were measured by bioassay. The antibiotic concentrations in serum obtained at the peak and at 1 and 6 h after the end of administration were as follows: group 1, teicoplanin, 26, 15.6, and 8.4 mg/liter; rifampin, not determined, 8.3, and 3.8 mg/liter; group 2, teicoplanin, 66, 29.4, and 11.5 mg/liter; rifampin, 14.8, 3.8, and 1.2 mg/liter. Higher median SBAs were obtained after treatment with rifampin than after that with teicoplanin. No interaction was observed between rifampin and teicoplanin. This was confirmed by determination of the killing rate in serum. Teicoplanin killed more slowly than rifampin. The combination had the same killing rate as rifampin alone. Rifampin neither improved nor antagonized the bactericidal activity of teicoplanin, as determined by the SBAs or the rate of killing.     

Measurement of ampicillin, vancomycin, linezolid and gentamicin activity against enterococcal biofilms

BACKGROUND: Enterococci frequently cause biofilm infections but susceptibility of clinical isolates growing in biofilms has not been investigated. The minimum biofilm eradicating concentration (MBEC) has been suggested as a guide to treatment of biofilm infections. We measured an alternative endpoint, the minimum biofilm inhibitory concentration (MBIC) and compared the results with MIC and MBC. OBJECTIVES: To compare the MIC, MBC and MBIC of ampicillin, vancomycin and linezolid against enterococcal biofilms, to assess the impact of additional gentamicin and correlate findings with clinical outcome. METHODS: MIC and MBC were measured using standard techniques. MBICs were measured using a modification of the Calgary biofilm device method. Fifty-eight enterococcal isolates from episodes of intravascular catheter-related bloodstream infection were tested. RESULTS: Tolerance to ampicillin, vancomycin and linezolid was seen in 93%, 100% and 93% of isolates, respectively. MIC(90)s of ampicillin, vancomycin and linezolid were all 4 mg/L for Enterococcus faecalis isolates. MBC(90)s of ampicillin, vancomycin and linezolid for E. faecalis isolates were 1024, >128 and 2048 mg/L, respectively. MBIC(90)s of ampicillin, vancomycin and linezolid for E. faecalis isolates were 8192, 4096 and 4096 mg/L, respectively. Results for Enterococcus faecium were similar for vancomycin and linezolid but this species was generally more resistant to ampicillin. Adding 10 mg/L gentamicin had a variable effect on MIC, MBC or MBIC, which was not predictable by gentamicin susceptibility on disc testing. CONCLUSIONS: Very high concentrations of ampicillin, vancomycin and linezolid are required to inhibit enterococcal biofilms in vitro. Combining these agents with gentamicin significantly reduced MIC, MBC and MBIC against only a proportion of enterococcal isolates. No correlation between MBIC and outcome was found.     

Bactericidal activity of vancomycin, daptomycin, ampicillin and aminoglycosides against vancomycin-resistant Enterococcus faecium

Daptomycin, vancomycin, ampicillin and aminoglycosides, alone or in combination, were tested for their bactericidal activity against 15 isolates of vancomycin-resistant Enterococcus faecium from immunocompromised children. The kill-kinetic studies at clinically achievable concentrations demonstrated that daptomycin alone or in combination with ampicillin had the greatest bactericidal activity.     

Comparative in vitro activities of teicoplanin, vancomycin, oxacillin, and other antimicrobial agents against bacteremic isolates of gram-positive cocci.

The in vitro activities of teicoplanin and vancomycin were compared with those of six other antimicrobial agents against 460 bacteremic isolates of gram-positive cocci. Teicoplanin was as active as vancomycin but less active than ciprofloxacin against staphylococci. Teicoplanin was the most potent of all agents tested against enterococci and had excellent activity against pneumococci.     

Comparative serum bactericidal activity against test anaerobes in volunteers receiving imipenem, clindamycin, latamoxef and metronidazole

Ten healthy volunteers received on separate days the following regimens: imipenem 500 mg, clindamycin 600 mg, latamoxef 1 g, and metronidazole 500 mg. The antibiotics were given intravenously as an infusion over 15 min. Blood samples were obtained before and 30 min, 1 and 6 h after the start of the infusion. Serum bacteriostatic and bactericidal activities were measured against the following strains of strict anaerobes: two strains of Bacteroides fragilis, one strain each of B. vulgatus, B. thetaiotaomicron, B. oralis, Fusobacterium symbiosum, Eubacterium lentum, Clostridium perfringens, and Peptostreptococcus magnus. Sera from patients receiving clindamycin showed the highest inhibitory and bactericidal activities except against B. thetaiotaomicron and F. symbiosum. Imipenem had similar inhibitory and bactericidal activity to that shown by latamoxef. Metronidazole had a moderate activity against all strains although the activity persisted for 6 h. Latamoxef was the most active antibiotic against the test strain of C. perfringens.     

Comparative killing activity and postantibiotic effect of streptomycin combined with ampicillin, ciprofloxacin, imipenem, piperacillin or vancomycin against strains of Streptococcus faecalis and Streptococcus faecium

Nine strains of Streptococcus faecalis and Streptococcus faecium were studied with respect to ampicillin, ciprofloxacin, imipenem, piperacillin, vancomycin and streptomycin. Two strains were highly resistant (MIC greater than or equal to 2,000 micrograms/ml) to streptomycin. Evaluation and comparison of the killing activity with killing curves, and duration of the postantibiotic effect (PAE) after exposure for 1 h with regrowth curves was done with combinations of antibiotics or alone. The overall killing effect of ciprofloxacin with streptomycin was antagonistic, whereas synergism (greater than or equal to one log10 decrease in viable counts) was observed in streptomycin-susceptible strains with combinations of streptomycin and ampicillin, imipenem, piperacillin or vancomycin. In addition, prolongation of PAE (greater than or equal to 0.5 h) was seen only in streptomycin-susceptible strains. Thus, seven (100%) strains showed a synergistic increase in PAE to combinations with ampicillin and vancomycin, three (43%) to imipenem, four (57%) to piperacillin, but none to the combination of streptomycin and ciprofloxacin. A significant correlation was observed between the magnitude of increased killing and the extent of increase in recovery period with combinations of streptomycin with either ampicillin or vancomycin.     

In vitro activity and killing effect of uperin 3.6 against gram-positive cocci isolated from immunocompromised patients

The in vitro activity of uperin 3.6, alone or combined with six antibiotics, against gram-positive cocci, including Rhodococcus equi, methicillin-resistant staphylococci, and vancomycin-resistant enterococci, was investigated. All isolates were inhibited at concentrations of 1 to 16 mg/liter. Synergy was demonstrated when uperin 3.6 was combined with clarithromycin and doxycycline.     

Interaction between penicillin, clindamycin or metronidazole and gentamicin against species of clostridia and anaerobic and facultatively anaerobic gram-positive cocci

Seven anaerobic and facultative Gram-positive cocci and 12 clostridial species were tested for in-vitro and in-vivo susceptibilities to penicillin, clindamycin, and metronidazole, used singly or in combination with gentamicin. The in-vitro tests consisted of determination of minimal inhibitory concentration (MIC), done without or with constant amounts of gentamicin. When used alone or in combination with penicillin or metronidazole, gentamicin had negligible effects on the bacteria. When used with clindamycin, gentamicin significantly reduced the MIC for one strain each of Peptococcus magnus and Clostridium difficile. The in-vivo tests were carried out in mice and consisted of studying the bacterial contents of abscesses induced by subcutaneous injection of bacterial suspensions. Synergy between gentamicin and penicillin, clindamycin or metronidazole was shown respectively in five, three and one strain. Consistency between in-vitro and in-vivo findings was present in the above mentioned strains only between gentamicin and clindamycin. The synergy between penicillin, clindamycin or metronidazole and gentamicin in Gram-positive anaerobic and facultative organisms may have clinical implications.     

In vitro activity of RPR 106972 alone and in combination with vancomycin,ampicillin, and gentamicin against multidrug-resistant enterococci

This investigation used checkerboard and time-kill assays to evaluate the in vitro activity of RPR 106972 (45% pristinamycin IB and 55% pristinamycin IIB) alone and in combination with vancomcyin or ampicillin ± gentamicin against multidrug-resistant enterococci. The checkerboard procedure resulted in synergistic or additive effects in 91% of the isolates with the combination of RPR 106972 plus vancomycin versus 68% with RPR 106972 plus ampicillin. The addition of gentamicin to either combination resulted in synergistic or additive results in 100% of the isolates. Inhibitory activity was observed with the time-kill assay with mean change in log₁₀ CFU/mL at 24 h of −0.31 for RPR 106972, 3.3 for vancomycin, −0.46 for RPR 106972 plus vancomycin, and −0.35 for RPR 106972 plus vancomycin and gentamicin. No antagonism was noted with any of the combinations. RPR 106972 demonstrates good inhibitory activity against Enterococcus faecium and may prove useful in the treatment of enterococcal infections.     

Comparative in vitro activity of teicoplanin and vancomycin against United States teicoplanin clinical trial isolates of gram-positive cocci.

In this study, the in vitro activity of teicoplanin and vancomycin was directly compared against 503 Gram-positive cocci isolated during the U.S. teicoplanin clinical trials. Both antibiotics were equally active against oxacillin-sensitive Staphylococcus aureus, oxacillin-sensitive and oxacillin-resistant Staphylococcus epidermidis, and other coagulase-negative staphylococci, except Staphylococcus haemolyticus. Teicoplanin was fourfold more active than vancomycin against oxacillin-resistant S. aureus (MIC90, 0.5 vs. 2.0 micrograms/ml), whereas vancomycin was more active than teicoplanin (MIC90, 2.0 vs. 8.0 micrograms/ml) against oxacillin-resistant S. haemolyticus. Teicoplanin was two- to eightfold more active than vancomycin against the streptococci and enterococci tested.     

Novel antibiotic regimens against Enterococcus faecium resistant to ampicillin, vancomycin, and gentamicin.

Enterococci have emerged as significant nosocomial pathogens. Enterococci with resistance to commonly used antibiotics are appearing more frequently. We encountered at our institution several infections caused by Enterococcus faecium with high-level resistance to ampicillin, vancomycin, and gentamicin. The optimal antibiotic therapy for serious infections with unusually resistant enterococci has not been established. Using time-kill studies, we tested the effectiveness of various antibiotic combinations against 15 isolates of multidrug-resistant enterococci. No antibiotic was consistently effective when used alone. The combination of ampicillin plus ciprofloxacin was bactericidal for the 12 isolates for which the ciprofloxacin MIC was < or = 8 micrograms/ml. The combination of ciprofloxacin plus novobiocin also demonstrated activity against these isolates. No combination was found to be bactericidal for the remaining three isolates, which were highly ciprofloxacin resistant. These antibiotic combinations may be important for the future treatment of serious infections caused by these resistant pathogens.     

In vitro activity of daptomycin versus linezolid and vancomycin against gram-positive uropathogens and ampicillin against enterococci, causing complicated urinary tract infections

OBJECTIVES: The existing therapeutic options for complicated urinary tract infections (UTI) caused by gram-positive uropathogens are not always optimal. Therefore, newer antimicrobials have to be assessed. METHODS: The antimicrobial activity of daptomycin was tested versus linezolid, vancomycin, and ampicillin (enterococci on ly), against pathogens from three different collections: (1) Uropathogens from hospitalized urological patients with complicated and/or hospital-acquired UTIs of the Urologic Clinic, Hospital St. Elisabeth, Straubing. (2) Uropathogens from a multicenter study comprising 37 urological centers throughout Germany. (3) Methicillin-resistant Staphylococcus aureus (MRSA) isolates of patients and staff within the Hospital St. Elisabeth, Straubing. Genotyping of the latter isolates was performed by pulsed-field gel electrophoresis. The minimal inhibitory concentrations (MIC) of daptomycin, linezolid, vancomycin, and ampicillin (only tested against enterococci) were determined by an agar dilution method using a multipointer with an inoculum of 10(4) CFU per point. RESULTS: For all methicillin-susceptible Staphylococcus aureus (n = 25), MRSA (n = 49), methicillin-susceptible coagulase-negative staphylococci (n = 129), methicillin-resistant coagulase-negative staphylococci (n = 33), for Enterococcus faecalis (n = 289), and for Enterococcus faecium (n = 4) the MICs ranged up to 2 mg/l (daptomycin, linezolid), up to 4 mg/l (vancomycin), and up to 8 mg/l (ampicillin, enterococci only) indicating that all strains were susceptible to the antibiotics tested. CONCLUSIONS: According to the in vitro activity daptomycin may be considered a promising antibacterial agent for the treatment of complicated UTI caused by gram-positive uropathogens. Thus, daptomycin should be evaluated in a clinical study.     

Synergistic activity between vancomycin or teicoplanin and gentamicin or tobramycin against pathogenic diphtheroids.

The in vitro activities of vancomycin and teicoplanin alone and in combination with gentamicin or tobramycin were studied by time-kill techniques with 11 strains of pathogenic diphtheroids (Corynebacterium group JK). The activities of vancomycin and teicoplanin were similar (MIC for 90% of strains tested [MIC90], 1 microgram/ml), as were those of gentamicin and tobramycin (the MIC90 was 1 microgram/ml for five aminoglycoside-susceptible strains, and the MIC90 was greater than 1,024 micrograms/ml for six aminoglycoside-resistant strains). No consistent synergistic killing could be demonstrated by the combination of glycopeptide and aminoglycoside antibiotics at arbitrarily chosen concentrations within the range of clinically achievable levels. However, by careful adjustment of both vancomycin and gentamicin concentrations within a narrow range below the MIC of each antibiotic, synergistic killing could be seen with an aminoglycoside-susceptible strain but not with an aminoglycoside-resistant strain. Synergism between glycopeptide and aminoglycoside antibiotics occurs with some diphtheroid organisms, but it may not be clinically relevant.     

Inconsistent bactericidal activity of triple-combination therapy with vancomycin, ampicillin, and gentamicin against vancomycin-resistant, highly ampicillin-resistant Enterococcus faecium.

Combination therapy with ampicillin, vancomycin, and gentamicin in vitro against several clinical isolates of vancomycin-resistant, highly ampicillin-resistant Enterococcus faecium, including VanA and VanB strains, was evaluated. The MICs of ampicillin were not significantly decreased by induction with vancomycin, and the combination of ampicillin and vancomycin was not inhibitory for any strain. Triple-combination therapy was least active against highly resistant VanA isolates, achieving a reduction of less than 1 log CFU at 24 h, but demonstrated slightly more activity against VanB strains.     

Reversal of activity of trimethoprim against gram-positive cocci by thymidine, thymine and 'folates'

The reversal of the antibacterial activity of trimethoprim against different species of Gram-positive cocci (Staphylococcus aureus, Staph. epidermidis, Staph. saprophyticus, group B streptococci, Streptococcus faecalis and Str. faecium) by thymine, thymidine and various 'folates' (folate, folinate, dihydrofolate and tetrahydrofolate) was tested. Against group B streptococci and staphylococci only thymidine antagonized trimethoprim. However, for enterococci, thymine, thymidine, dihydrofolate, tetrahydrofolate and folinate all reversed the activity of trimethoprim, although by different amounts. Dihydrofolate was significantly more effective as a trimethoprim antagonist for Str. faecium than for Str. faecalis. While thymine and thymidine caused the MIC of trimethoprim against enterococci to increase more than 100-fold--thereby rendering them resistant--the 'folates' brought about much smaller increases in trimethoprim MIC, in the order of ten-fold only. Thus, even in the presence of 'folates' enterococci remain sensitive in vitro to trimethoprim.     

利奈唑胺对革兰阳性球菌的体外抗菌活性研究

目的 检测利奈唑胺对临床分离的金黄色葡萄球菌、表皮葡萄球菌、溶血葡萄球菌、粪肠球菌、屎肠球菌等革兰阳性球菌的体外扰菌活性.为临床合理使用抗生素提供依据.方法 采用VITEK-32全自动微生物分析仪和ATB自动微生物分析仪鉴定和药敏系统对临床分离的常见革兰阳性球菌267株进行鉴定和药敏试验.根据其药敏结果 比较8种抗菌药物对葡萄球菌、肠球菌的抗菌活性.结果 在临床分离的267株菌中金黄色葡萄球菌111株,MRSA 74株(占66.7%).凝同酶阴性葡萄球菌96株(表皮葡萄球菌57株、溶血葡萄球菌39株),MRCNS有80株(占86.0%),粪肠球菌45株,屎肠球菌13株.利奈唑胺对207株葡萄球菌、58株肠球菌体外抗菌活性分别为100%、93.1%,与万古霉素相当,明显高于其他常用的抗生索(如红霉素、头孢唑林、环丙沙星等).其对金黄色葡萄球菌、凝同酶阴性葡萄球菌、肠球菌的MIC50和MIC90分别为1,1mg/L;1,1mg/L;2,4mg/L.结论 耐甲氧西林葡萄球菌发生率高,多重耐药严重,利奈唑胺对葡萄球菌的抗菌活性与万占霉索相当,对肠球菌也有较强的抗菌活性.葡萄球菌、肠球菌对左氧氟沙星、四环素、红霉素均产生了不同程度的耐药性.